{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:14:06Z","timestamp":1786115646358,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council-Taiwan","award":["114-2320-B-039-010-"],"award-info":[{"award-number":["114-2320-B-039-010-"]}]},{"name":"National Health Research Institute-Taiwan","award":["#NHRI-EX115-11403BI"],"award-info":[{"award-number":["#NHRI-EX115-11403BI"]}]},{"DOI":"10.13039\/501100012544","name":"China Medical University-Taiwan","doi-asserted-by":"crossref","award":["#CMU113-MF-01"],"award-info":[{"award-number":["#CMU113-MF-01"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science and Technology Council-Taiwan","award":["113-2811-B-039 -018"],"award-info":[{"award-number":["113-2811-B-039 -018"]}]},{"name":"Taiwan Bio-development Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Here, we report the identification of a previously unrecognized population of tumor-induced podoplanin-positive (PDPN+) cells in clear-cell renal cell carcinoma (ccRCC) that exhibit features of under-differentiated lymphatic endothelial cells (LECs). These PDPN+ cells lack a complete repertoire of canonical LEC markers, including VE-cadherin, LYVE1, and VEGFR3, and fail to form functional lymphatic vessels, indicating a dysplastic phenotype. We termed these cells dysLECs and found that these cells are induced by BMP10 produced specifically by tumor cells. In turn, dysLECs secrete CXCL13, which promotes tumor cell proliferation and metastasis. Ligand-receptor analyses revealed a highly tumor-specific reciprocal signaling circuit: kidney tubule cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene uniquely express BMP10, a TGF-\u03b2 family cytokine, whereas its receptor ALK1 is restricted to dysLECs; conversely, dysLECs produce CXCL13, while VHL mutant kidney tubule cells uniquely express its receptor, CXCR5. Pharmacological inhibition of ALK1 reduced CXCL13 production and suppressed the hyperplastic phenotype of VHL mutant tumor cells in vivo, whereas BMP10 neutralization inhibited tumor growth and metastasis in an orthotopic ccRCC xenograft model. Collectively, these findings identify a dysplastic population of PDPN+ lymphatic-like endothelial cells and define a tumor-specific BMP10-CXCL13 signaling axis that drives ccRCC progression, uncovering a previously unrecognized therapeutic vulnerability in this disease.<\/jats:p>","DOI":"10.3390\/ijms27156994","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:15:22Z","timestamp":1785834922000},"page":"6994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor-Induced PDPN+ Lymphatic-like Endothelial Cells Promote Clear-Cell Renal Cell Carcinoma Progression Through Reciprocal BMP10-CXCL13 Signaling"],"prefix":"10.3390","volume":"27","author":[{"given":"Tuong-Vi","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Engineering, National Central University, 300 Zhongda Rd., Taoyuan City 320317, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-2443","authenticated-orcid":false,"given":"Hieu-Huy","family":"Nguyen-Tran","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University-Taiwan, 91 Hsueh-Shih Rd., Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi-Ngoc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University-Taiwan, 91 Hsueh-Shih Rd., Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2308-4297","authenticated-orcid":false,"given":"Tien","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Engineering, National Central University, 300 Zhongda Rd., Taoyuan City 320317, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University-Taiwan, 91 Hsueh-Shih Rd., Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17009","DOI":"10.1038\/nrdp.2017.9","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. 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